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• Early mesothelioma diagnosis is challenging, especially on cytology. • Pleural effusions offer a useful resource of mesothelial cells for diagnosis. • BAP1 and CDKN2A losses are diagnostically relevant molecular alterations. • IHC and FISH improve diagnosis in all sample types but need validation. • Analysis of gene expression profiles may improve diagnosis. Pathology plays an important role in diagnosing mesothelioma since radiological and clinical findings alone cannot distinguish mesothelioma reliably from its many mimics. The long-held gold standard for pathological diagnosis requires a tissue biopsy that, in addition to mesothelial phenotype, demonstrates invasion, but this is challenged by the WHO recognition of mesothelioma in situ (MIS) and concurrent acknowledgement of all mesotheliomas as malignant. Tumor sampling and ancillary techniques are of paramount importance for diagnosis of MIS. Standardisation of these techniques, cut-off points and terminology, and an updated staging system are urgently required. These clinically relevant issues and the impact of new developments were illustrated at the pathology session of 15th meeting of the International Mesothelioma Interest Group. It was reported that combination of losses in p16 nuclear expression, with cut-off ≤ 1%, and cytoplasmic MTAP with cut-off ≥ 30% demonstrated increased specificity (96%) and high sensitivity (86%) for CDKN2A HD detection. Otherwise, the combination of p16 IHC and CDKN2A HD may improve prognosis. The potential usefulness of pleural effusions for early diagnosis was demonstrated in a retrospective study investigating pleural effusions had been diagnosed as benign prior to mesothelioma diagnosis. Alterations of BAP1 (IHC) and CDKN2A (FISH) were detectable 2 or more years prior diagnosis. Moreover, analysis of gene expression profiles in cytology samples by principal component analysis discriminated reactive hyperpasia from epitheliod mesothelioma. Early diagnosis, including cytology diagnosis, is being acyively investigated. Since no treatment recommendations exist for MIS, pathologists recognise the need for international collaborations to fully characterise this rare entity. Clear communication with the clinical teams is required to ensure optimum patient care. The data reported in this meeting are encouraging and open avenues for further work that will allow even earlier diagnosis and better characterisation of mesothelioma progression, based on changes in gene expression, including epigenetic changes. [ABSTRACT FROM AUTHOR]

Highlights • Three signal pathway inhibitors show higher toxicities than cisplatin: verteporfin, defactinib and NSC668394. • Verteporfin sensitivity is related to molecular classification in subgroups. • Verteporfin inhibits cell viability independently of YAP. • Defactinib sensitivity is related to FAK protein kinase activation. • Predictive biomarkers of inhibitors response were defined based on gene expression. Abstract Objectives Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response. Materials and methods The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers. Results Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors. Conclusion Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response. [ABSTRACT FROM AUTHOR]

Abstract: Epidemiological studies have shown that asbestos fibers constitute the major occupational risk factor and that asbestos acts synergistically with tobacco smoking to induce lung cancer. Although some somatic gene alterations in lung cancer have been linked to tobacco smoke, few data are available on the role of asbestos fibers. P16/CDKN2A is an important tumor suppressor gene that is frequently altered in lung cancer via promoter 5′-CpG island hypermethylation and homozygous deletion, and rarely via point mutation. Many studies suggest that tobacco smoking produces P16/CDKN2A promoter hypermethylation in lung cancer, but the status of this gene in relation to asbestos exposure has yet to be determined. The purpose of this study was to investigate the mechanism of P16/CDKN2A alterations in lung cancer in asbestos-exposed patients. P16/CDKN2A gene status was studied in 75 human non-small-cell lung cancer (NSCLC) cases with well-defined smoking habits, and detailed assessment of asbestos exposure, based on occupational questionnaire and determination of asbestos bodies in lung tissue. The results of this study confirm published data on the effect of tobacco smoke on P16/CDKN2A gene alterations, characterized by significantly higher P16/CDKN2A promoter hypermethylation in heavy smokers (more than 40 pack-years (P-Y)) than in smokers of less than 40 P-Y. These results also demonstrate a higher incidence of loss of heterozygosity and homozygous deletion in asbestos-exposed cases, after adjustment for age and cumulative tobacco consumption, than in unexposed cases (P =0.0062). This study suggests that P16/CDKN2A gene inactivation in asbestos-exposed NSCLC cases mainly occurs via deletion, a feature also found in malignant mesothelioma, a tumor independent of tobacco smoking but associated with asbestos exposure, suggesting a possible relationship with an effect of asbestos fibers. [Copyright &y& Elsevier]